The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting almost one in ten individuals over the age of 65, accounts for over 50% of senile dementia and the majority of pre-senile dementia cases, and is characterized by progressive deterioration of higher cognitive functions, including the loss of memory. AD is typically characterized by accumulation of β-amyloid plaques and neurofibrillary tangles (NFT) in the brain and many neurodegenerative effects of AD appear to be closely linked to amyloid production. In addition to these specific neuropathological features, AD brains exhibit extensive cellular atrophy and cell loss, shrinkage of cortical thickness, enlargement of sulci and ventricles, and changes in multiple neurochemical systems including acetylcholine (ACh), glutamate, GABA and serotonin. There is increasing effort to see if all features/symptoms of AD can be associated with the accumulation of amyloid plaques and tangles.
With increasing efforts to find treatments and a cure for AD, there is much research into imaging plaques and NFT essential to the diagnosis and clinical management of AD. More recently, various 18F agents have been developed to enable more wide-spread use of amyloid PET imaging, and efforts are currently underway for the development and evaluation of NFT PET imaging agents.
For example, one class of PET imaging agents comprises substituted aminonaphthalene backbones that have been shown to target the polymeric form of the β-amyloid peptide that is associated with senile plaques and bind to neurofibrillary tangles. Most prominently, 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphtyl}ethylidene)malonitrile (known as [18F]FDDNP), became the first diagnostic tool to image plaques and tangles with relatively high specificity (see e.g., U.S. Pat. Nos. 6,274,119 and 6,660,530). Further related compounds are described in U.S. Pat. App. No. 2007/0053831. However, [18F]FDDNP is highly lipophilic and consequently exhibits some nonspecific binding. Therefore, the results obtained from PET scans using [18F]FDDNP are often relatively poor in image quality and make diagnosis difficult. These and all other referenced extrinsic materials are incorporated herein by reference in their entirety. Where a definition or use of a term in a reference that is incorporated by reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein is deemed to be controlling.
Still other known labeling compounds include numerous substituted and radiolabeled benzofuran compounds as described, for example, in U.S. Pat. No. 7,173,061, and numerous substituted quinolinehydrazones as described, for example, in U.S. Pat. No. 6,589,504. Various substituted phenyl imidazo[1,2-b]pyridazine and similar structures are described as imaging agents in WO 2007/033080, and selected substituted benzathiazole compounds are known for labeling and are described in WO 2007/035405. Still further known compounds with more or less specific binding to amyloid are referred to in U.S. Pat. App. No. 2005/0048000. However, and similarly to FDDNP, such known compounds are often problematic with respect to their transport across the blood-brain barrier, stability under physiological conditions, and selectivity towards neurofibrillary tangles and/or senile plaques.
Significant advances have been made in plaque imaging, for example using 11C-PIB, and Prior Art FIG. 1A depicts the chemical structure of 11C-PIB. However, little PIB binding was seen in PS1/APP transgenic mice brain despite the substantial amount of Aβ plaques using 11C-PIB. More recently, microPET imaging in APP23 transgenic mice has yielded better results on Aβ-plaque localization using high specific activity 11C-PIB. Thus, there is continued interest in the further development of Aβ-plaque imaging agents. Among those are imaging agents that are labeled with fluorine-18, which may provide a higher target to non-target ratio. For example, such agents include 18F-Florbetapir, 18F-Flutmetamol, and 18F-Florbetaben.
Likewise, advances have also been made in tangle imaging agents. For example, the first agent developed was fluorine-18 labeled FDDNP which is being used for imaging plaques and tangles. 18F-FDDNP is highly lipophilic (log P>3) due to its structure, particularly the naphthalene ring which gives low target to non-target ratios. This results in poor image quality and makes diagnosis difficult; however 18F-FDDNP is currently one of the few radiotracers suitable for NFT imaging (Shin et al., 2011). Prior Art FIG. 1B depicts the chemical structure of 18F-FDDNP.
Numerous efforts are also currently underway to develop NFT imaging agents that may provide improved in vivo properties. Quinoline and benzimidazole derivatives have been reported to show selectivity for NFT. Over the past few decades traumatic brain injury (TBI) has become a major public health problem that is associated with significant medical and psychological morbidity and socioeconomic costs. Importantly, TBI from improvised explosive devices and other destructive weapons has become the signature injury of the current wars in Afghanistan and Iraq. Significant amount of resources have been allocated toward understanding the underlying basis of TBI and developing effective neuroprotective therapies, particularly for mild TBI (mTBI). However, large gaps remain in basic knowledge and ability to prevent many of the long-term consequences of mTBI. Among the major obstacles preventing progress are the lack of standardized tools for accurate diagnosis of mTBI, and to physiologically monitor the course of the disease and response to treatment. Notably, animal models of mTBI and human post-mortem brain tissue from individuals with chronic traumatic encephalopathy have established a strong link between TBI and abnormal deposition of tau protein in the brain, which is also a major pathological hallmark of Alzheimer's disease. Unfortunately, the only way to reliably evaluate the status of tau deposition in the brain currently is by post-mortem analysis.
The inventors have recently have developed FBM (4′-[(2-fluoroethyl)(methyl)amino]-4-phenyl-3-buten-2-malonitrile) for NFT imaging. The ability to image tau deposits in the brain will significantly improve the understanding of the role played by tau in the pathophysiology of TBI. Tau imaging could directly impact the detection, diagnosis and treatment of mTBI and help in further understanding AD. Prior Art FIG. 1C shows the chemical structure of 18F-FBM. However, 18F-FBM may not fully satisfy all requirements for imaging of plaque and NFT in AD. Further known imaging agents for β-amyloid plaques are disclosed in US 2003/0138374.
Thus, even though various imaging compositions and methods are known in the art, all or almost all of them suffer from one or more disadvantages. Moreover, current use of the known imaging agents is limited to β-amyloid plaques and/or neurofibrillary tangles. Therefore, there is still a need for improved compositions and methods of beta-amyloid imaging compounds and compositions.